Temozolomide, Gemcitabine, and Decitabine Hybrid Nanoconjugates: From Design to Proof-of-Concept (PoC) of Synergies toward the Understanding of Drug Impact on Human Glioblastoma Cells

Sahli, Ferdaous; Courcelle, Manon; Palama, Tony; Djaker, Nadia; Savarin, Philippe; Spadavecchia, Jolanda

doi:10.1021/acs.jmedchem.0c00694

Cited by 22 publications

(15 citation statements)

References 59 publications

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“…Here we show that TRC105 prolongs the anti-leukemic activity of DAC in AML xenografts, suggesting that TRC105 may provide beneficial effects to current treatment regimens for AML. While only DAC/TRC105 combination was examined in the present study, recent studies show that novel DAC nanocarrier has synergistic effects with chemotherapeutic reagents in various cancer models [ 28 , 29 , 30 ]. Further studies may be required to determine the most efficacious therapeutic combination, but our findings provide evidence for a novel combined regimen of DAC and TRC105 for AML, which may be particular benefit for AML patients who are unfit to standard induction therapy.…”

Section: Resultsmentioning

confidence: 99%

Therapeutic effect of TRC105 and decitabine combination in AML xenografts

Baik

Felices

Yingst

et al. 2020

Heliyon

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Acute myeloid leukemia (AML) is an aggressive hematologic malignancy, often characterized by poor prognosis following standard induction therapy. The hypomethylating agent decitabine (DAC) is an alternative treatment for elderly and relapsed/refractory AML patients, yet responses following DAC monotherapy are still modest. The transforming growth factor-β (TGF-β) receptor CD105 (endoglin) is expressed in various hematopoietic malignancies, and high CD105 expression correlates with poor prognosis in AML patients. Using a xenograft model, we have recently demonstrated that targeting CD105 + AML blasts with the TRC105 monoclonal antibody inhibits leukemia progression. Here we investigated whether administration of TRC105 along with DAC could represent a novel therapeutic option for relapsed/refractory AML. Our data show that the DAC/TRC105 combination results in a more durable anti-leukemic effect in AML xenografts compared to DAC monotherapy. Moreover, the DAC/TRC105 combination enhanced reactive oxygen species (ROS) activity, which correlated with reduced leukemia burden. RNA-sequencing studies suggest that TRC105 may alter TGF-β activity in AML blasts. Taken together, these findings provide rationale for the clinical evaluation of TRC105 in combination with DAC in AML patients.

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Section: Resultsmentioning

confidence: 99%

Therapeutic effect of TRC105 and decitabine combination in AML xenografts

Baik

Felices

Yingst

et al. 2020

Heliyon

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“…Three chemotherapy drugs decitabine, gemcitabine, and temozolomide were loaded on gold nanoparticles via electrostatic interactions and targeted to U87 human malignant Glial cells following the mechanism of cell-mediated transport. This delivery system integrated the synergistic effect of three drugs and showed a significant therapeutic effect on glioma with a reduction in resistance of glioma cells to temozolomide (Sahli et al., 2020 ). In addition to drugs, genes delivery was also supported through the aid of gold nanoparticles.…”

Section: Nano – Based Brain Cancer Targetingmentioning

confidence: 99%

Combinatorial therapeutic strategies for enhanced delivery of therapeutics to brain cancer cells through nanocarriers: current trends and future perspectives

Wang

Liu

et al. 2022

Drug Delivery

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Brain cancer is the most aggressive one among various cancers. It has a drastic impact on people's lives because of the failure in treatment efficacy of the currently employed strategies. Various strategies used to relieve pain in brain cancer patients and to prolong survival time include radiotherapy, chemotherapy, and surgery. Nevertheless, several inevitable limitations are accompanied by such treatments due to unsatisfactory curative effects. Generally, the treatment of cancers is very challenging due to many reasons including drugs’ intrinsic factors and physiological barriers. Blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) are the two additional hurdles in the way of therapeutic agents to brain tumors delivery. Combinatorial and targeted therapies specifically in cancer show a very promising role where nanocarriers’ based formulations are designed primarily to achieve tumor-specific drug release. A dual-targeting strategy is a versatile way of chemotherapeutics delivery to brain tumors that gets the aid of combined ligands and mediators that cross the BBB and reaches the target site efficiently. In contrast to single targeting where one receptor or mediator is targeted, the dual-targeting strategy is expected to produce a multiple-fold increase in therapeutic efficacy for cancer therapy, especially in brain tumors. In a nutshell, a dual-targeting strategy for brain tumors enhances the delivery efficiency of chemotherapeutic agents via penetration across the blood-brain barrier and enhances the targeting of tumor cells. This review article highlights the ongoing status of the brain tumor therapy enhanced by nanoparticle based delivery with the aid of dual-targeting strategies. The future perspectives in this regard have also been highlighted.

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“…They stop the cell cycle in the G2/M phase by subjecting DNA to alkylation. According to research data, TMZ had a greater effect in combination with GEM [ 111 , 112 , 113 ].…”

Section: Nanoscale Delivery Systemsmentioning

confidence: 99%

Temozolomide Efficacy and Metabolism: The Implicit Relevance of Nanoscale Delivery Systems

et al. 2022

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The most common primary malignant brain tumors in adults are gliomas. Glioblastoma is the most prevalent and aggressive tumor subtype of glioma. Current standards for the treatment of glioblastoma include a combination of surgical, radiation, and drug therapy methods. The drug therapy currently includes temozolomide (TMZ), an alkylating agent, and bevacizumab, a recombinant monoclonal IgG1 antibody that selectively binds to and inhibits the biological activity of vascular endothelial growth factor. Supplementation of glioblastoma radiation therapy with TMZ increased patient survival from 12.1 to 14.6 months. The specificity of TMZ effect on brain tumors is largely determined by special aspects of its pharmacokinetics. TMZ is an orally bioavailable prodrug, which is well absorbed from the gastrointestinal tract and is converted to its active alkylating metabolite 5-(3-methyl triazen-1-yl)imidazole-4-carbozamide (MTIC) spontaneously in physiological condition that does not require hepatic involvement. MTIC produced in the plasma is not able to cross the BBB and is formed locally in the brain. A promising way to increase the effectiveness of TMZ chemotherapy for glioblastoma is to prevent its hydrolysis in peripheral tissues and thereby increase the drug concentration in the brain that nanoscale delivery systems can provide. The review discusses possible ways to increase the efficacy of TMZ using nanocarriers.

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Temozolomide, Gemcitabine, and Decitabine Hybrid Nanoconjugates: From Design to Proof-of-Concept (PoC) of Synergies toward the Understanding of Drug Impact on Human Glioblastoma Cells

Cited by 22 publications

References 59 publications

Therapeutic effect of TRC105 and decitabine combination in AML xenografts

Therapeutic effect of TRC105 and decitabine combination in AML xenografts

Combinatorial therapeutic strategies for enhanced delivery of therapeutics to brain cancer cells through nanocarriers: current trends and future perspectives

Temozolomide Efficacy and Metabolism: The Implicit Relevance of Nanoscale Delivery Systems

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